The US Environmental Protection Agency said it has terminated 388 employees hired over the last two years to align its workforce with Trump's "energy dominance" policy agenda.
Workers at the Departments of Interior, Energy, Veterans Affairs, Agriculture and Health and Human Services had their employment terminated in a drive that so far has largely - but not exclusively - targeted probationary employees in their first year on the job who have fewer employment protections.
Some agencies have been essentially shuttered, such as the independent watchdog the Consumer Financial Protection Bureau, where cuts also hit workers on fixed-term contracts.
The tax-collecting Internal Revenue Service is preparing to fire thousands of workers next week, two people familiar with the matter said, a move that could squeeze resources ahead of Americans' April 15 deadline to file income taxes.
The firings are in addition to the roughly 75,000 workers who have taken a buyout that Trump and Musk have offered to get them to leave voluntarily, according to the White House. That equals about three per cent of the 2.3 million-person civilian workforce.
Trump says the federal government is too bloated and too much money is lost to waste and fraud. The federal government has some $US36 ($A57) trillion in debt and ran a $US1.8 ($A2.8) trillion deficit in 2024, and there is bipartisan agreement on the need for reform.
Critics have questioned the blunt force approach of Musk, the world's richest person, who has amassed extraordinary influence in Trump's presidency.
US Treasury Secretary Scott Bessent on Friday shrugged off those concerns, comparing Musk's Department of Government Efficiency to a financial audit.
"These are serious people, and they're going from agency to agency, doing an audit, looking for best practices," he told Fox Business Network.
Fired federal workers expressed shock.
"I've done a lot for my country and as a veteran who served his country, I feel like I've been betrayed by my country," said Nick Gioia, who served in the army and worked for the Department of Defense for a total of 17 years. He joined the United States Department of Agriculture's Economic Research Service in December only to be fired late on Thursday.
"I don't feel like this has anything to do with federal workers, I feel like this is just a game," said Gioia, who lives in Elizabethtown, Kentucky, and has a child with epilepsy.
"To sit here and watch people like Mr Musk tweet out how he feels like he's doing a great job, he doesn't realise what he's doing to people's lives."
About 1200 to 2000 workers at the Department of Energy were laid off, including 325 from the National Nuclear Security Administration, which oversees the nuclear stockpile, sources familiar with the matter told Reuters on Friday.
But those layoffs have been "partly rescinded" to retain essential nuclear security workers, one of the sources said. It was unclear how many of the 325 firings were rescinded.
Another 2300 employees were axed from the Interior Department, which manages 500 million acres of public lands, including more than 60 national parks, as well as the country's on- and offshore oil and gas leasing programs, sources told Reuters.
An unknown number of workers at the Department of Agriculture were also shown the door, sources said.
The Centers for Disease Control and Prevention is cutting almost 1300 workers, or one-tenth of its staff, the Associated Press reported.
The firings added to a round of cuts that has targeted departments including Veterans Affairs, Education and the Small Business Administration.
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